Related Experiment Video

Updated: Jun 24, 2025

Reconstitution Of β-catenin Degradation In Xenopus Egg Extract
09:41

Reconstitution Of β-catenin Degradation In Xenopus Egg Extract

Published on: June 17, 2014

12.1K

Covalent Degrader of the Oncogenic Transcription Factor β-Catenin

Flor A Gowans1,2, Nafsika Forte1,2, Justin Hatcher1,2

  • 1Department of Chemistry, University of California, Berkeley, California 94720, United States.

Journal of the American Chemical Society
|June 7, 2024
PubMed

Insights

Researchers developed EN83, a novel compound that degrades the oncogenic transcription factor beta-catenin (CTNNB1) via a proteasome-dependent pathway. This covalent targeting approach offers a new strategy for cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Beta-catenin (CTNNB1) is a key oncogenic transcription factor implicated in cancer pathogenesis.
  • Targeting CTNNB1 pharmacologically has been a significant challenge in cancer research.

Purpose of the Study:

  • To identify novel compounds capable of degrading CTNNB1.
  • To explore covalent targeting strategies for challenging transcription factors.

Main Methods:

  • Screening of cysteine-reactive covalent ligands.
  • Identification and characterization of the monovalent degrader EN83.
  • Structural optimization of the lead compound.

Main Results:

  • EN83 was identified as a compound that depletes CTNNB1 through ubiquitin-proteasome degradation.
  • EN83 covalently targets CTNNB1 at cysteines C466, C520, and C619, causing destabilization.
  • An optimized degrader selectively targets C619, demonstrating high potency.

Conclusions:

  • Chemoproteomic approaches can successfully target and degrade challenging transcription factors like CTNNB1.
  • Destabilization-mediated degradation is a viable strategy for developing new cancer therapeutics.

More Related Videos

The Soft Agar Colony Formation Assay08:01

The Soft Agar Colony Formation Assay

Published on: October 27, 2014

111.6K
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells06:54

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

12.9K

Related Concept Videos

Catenins01:23

Catenins

Catenins are characterized by multiple binding domains and dynamic structures that allow them to function as linker proteins in cell junction complexes. All catenins, except α-catenin, contain a characteristic protein sequence called the armadillo repeat and are therefore also called armadillo proteins.
Catenins in Cell Junctions
Catenins bind to cell adhesion molecules such as cadherins and link them to different cytoskeletal proteins depending on the type of cell junction. At the...
2.3K
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
7.3K
Canonical Wnt Signaling Pathway02:54

Canonical Wnt Signaling Pathway

The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which...
8.7K
Anaphase Promoting Complex00:50

Anaphase Promoting Complex

The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
2.8K
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
6.8K
Cancer-Critical Genes I: Proto-oncogenes01:33

Cancer-Critical Genes I: Proto-oncogenes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
8.8K